The present invention is directed to the use of AZT derivatives and its analogs in providing contraceptive, e.g. spermicidal, effects. In one particular embodiment, the present invention is directed to novel dual-function derivatives of AZT that exhibit spermicidal activity and maintain potent anti-HIV activity.
The known spermicidal agents, nonoxynol-9 (N9) and gramicidin, exert their effects via a detergent-like ability to damage the sperm plasma membrane, perturb its conformation and destroy its semi-permeable nature thereby impairing the sperm motility and egg fertilizing functions (Wilborn, et al., Fertil Steril 1983; 39:717-719; Bourinbaiar, et al., Life Sci 1994; 54:PL 5-9). Because of their non-specific membrane disruptive properties, such vaginal spermicides have been shown to damage the cervicovaginal epithelium, as well, which may lead to a lower degree of protection from sexually transmitted diseases (Niruthisard, et al., Sex Transm Dis 1991; 18:176-179). A vaginal contraceptive that does not function with the non-specific membrane toxicity mediated by detergent-type action of the currently available vaginal contraceptives would be desirable.
In addition, the dangers of sexually-transmitted diseases have been widely recognized. However, despite the educational and preventive measures taken to date, the spread of diseases such as HIV remains a serious health problem. It would be desirable to provide a contraceptive that also provides some protection against sexually-transmitted diseases such as HIV, especially to reduce the risks for women who otherwise would be at high risk of acquiring such diseases by heterosexual transmission.
While AZT (3xe2x80x2-azido-3xe2x80x2-deoxythymidine; also known as zidovudine, or ZDV) has been widely studied for its activity against HIV infection, AZT itself has not been recognized as having any contraceptive, for example spermicidal and/or sperm-immobilizing, activity. The present invention provides AZT derivatives that are useful as contraceptive agents and products and methods using them. Examples of such products include vaginal foams, creams, lotions or gels, sponges or other vaginal inserts, and condom lubricating compositions. The present invention also is directed to certain AZT derivatives that exhibit the contraceptive properties while maintaining activity against HIV.
One aspect of the present invention is directed to AZT derivatives that include 5-halo and 6-alkoxy substitution on the thymine ring of AZT and exhibit contraceptive properties.
Some embodiments of the present invention are directed to providing a contraceptive effect using novel dual-function AZT derivatives with both anti-HIV and spermicidal activity that include 5-halo and 6-alkoxy substitution on the thymine ring of AZT and substitution on the pentose ring of AZT that facilitates entry of the compound into a cell. For example, among others, the substitution on the pentose ring can be with a phosphate group, which may be further substituted with an aryl-containing group, and the aryl group itself can be further substituted. In the above aspects of the invention, the azide group on the pentose ring of AZT can be replaced with NH2, which optionally can be substituted, or the azide group could be replaced with halo, CN, or COOH.
Some embodiments are directed to contraceptive products that use a spermicidal AZT derivative as an active agent, and to the production of such contraceptive products.
Some embodiments are directed to a method of contraception that includes a step of contacting sperm with a spermicidal AZT derivative, for example by means of a contraceptive product of this invention as discussed above.
Some embodiments include a compound of the following formula: 
where:
R1 is N3, NH2, NHxe2x80x94CH3, NHxe2x80x94COCH3, NHxe2x80x94Ph, NHxe2x80x94COPh, or NHxe2x80x94CH2xe2x80x94Ph;
R2 is halogen;
R3 is C1-3 alkoxy;
R4, R5, and R6 are the same or different and are selected from hydrogen, alkyl, aryl, alkoxy, halo, haloalkyl, arylalkyl, aralkoxy, haloalkoxy, nitro, cyano, and animo; and
Rxe2x80x3 is an amino acid residue;
or a pharmaceutically acceptable salt or ester thereof.
Some embodiments include a method of inhibiting conception in a mammal, comprising contacting mammalian sperm with an effective spermicidal amount of a compound of the above formula. Other embodiments include a method of inhibiting virus replication in a cell infected with virus, the method comprising administering to the infected cell a virus replication inhibiting amount of a compound of the above formula. Yet other embodiments include a pharmaceutical composition, comprising an effective spermicidal amount or antiviral amount of a compound of the above formula.